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Definitions

• the present invention relates to novel compounds of Formula (I), wherein X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , M 1 , M 2 , M 3 , A m and B n are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors - subtype 4 ("mGluR4") which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors.
• mGluR4 metabotropic glutamate receptors - subtype 4
• the invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.
• Glutamate is the major amino-acid transmitter in the mammalian central nervous system (CNS). Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration and regulation of cardiovascular function. Furthermore, glutamate is at the center of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.
• iGluRs ionotropic glutamate receptor channels
• mGluRs metabotropic glutamate receptors
• GPCRs G protein-coupled receptors
• the mGluR family is composed of eight members. They are classified into three groups (group I comprising mGluRl and mGluR5; group II comprising mGluR2 and mGluR3; group III comprising mGluR4, mGluR ⁇ , mGluR7 and mGluR8) according to sequence homology, pharmacological profile and nature of intracellular signalling cascades activated (Schoepp et al. (1999) Neuropharmacology, 38:1431-76).
• Glutamate activates the mGluRs through binding to the large extracellular amino- terminal domain of the receptor, herein called the orthosteric binding site. This activation induces a conformational change of the receptor which results in the activation of the G-protein and intracellular signalling pathways.
• mGluR4 receptors are expressed most intensely in the cerebellar cortex, basal ganglia, sensory relay nuclei of the thalamus and hippocampus (Bradley et al. (1999) Journal of Comparative Neurology, 407:33-46; Corti et al. (2002) Neuroscience, 110:403-420).
• the mGluR4 subtype is negatively coupled to adenylate cyclase via activation of the Goci/o protein, is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and activation of mGluR4 leads to decreases in transmitter release from presynaptic terminals (Corti et al.
• Orthosteric agonists of mGluR4 are not selective and activate the other Group III mGluRs (Schoepp et al (1999) Neuropharmacology 38: 1431-1476).
• the Group III orthosteric agonist L-AP4 was able to reduce motor deficits in animal models of Parkinson's disease (Valenti et al (2003) J. Neurosci. 23:7218-7226) and decrease excitotoxicity (Bruno et al (2000) J. Neurosci.
• mGluR4 is believed to be the most interesting novel drug target for the treatment of Parkinson's disease (for a review see Conn et al Nature Review Neuroscience 2005).
• Symptoms of Parkinson's disease appear to be due to an imbalance in the direct and indirect output pathways of the basal ganglia and reduction of transmission at the inhibitory GABAergic striato-pallidal synapse in the indirect pathway may result in alleviation of these symptoms (Marino et al. (2002) Amino Acids, 23:185-191).
• mGluR4 is more abundant in striato-pallidal synapses than in striata -nigral synapses, and its localization suggests function as a presynaptic heteroceptor on GABAergic neurons (Bradley et al. (1999) Journal of Comparative Neurology, 407:33-46) suggesting that selective activation or positive modulation of mGluR4 would decrease GABA release in this synapse thereby decreasing output of the indirect pathway and reducing or eliminating the Parkinson's disease symptoms.
• a new avenue for developing selective compounds acting at mGluRs is to identify molecules that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site.
• PHCCC a positive allosteric modulator of mGluR4 not active on others mGluRs (Maj et al (2003) Neuropharmacology 45:895-906), has been shown to be efficacious in animal models of Parkinson's disease thus representing a potential novel therapeutic approach for Parkinson's disease as well as for other motor disorders and disturbances (Marino et al (2003) Proc. Nat. Acad. Sci. USA 100:13668-13673), neurodegeneration in Parkinson's disease (Marino et al (2005) Curr. Topics Med. Chem.
• mGluR4 receptors which are expressed in ⁇ - and F cells in the islets of Langerhans inhibits glucagon secretion.
• Molecules which activate or potentiate agonist activity of these receptors may be an effective treatment for hyperglycemia, one of the symptoms of type 2 diabetes (Uehara et al (2004) Diabetes 53:998-1006).
• ⁇ -chemokine RANTES is importantly involved in neuronal inflammation and has been implicated in the pathophysiology of multiple sclerosis.
• Activation of Group III mGluRs with L-AP4 reduced the synthesis and release RANTES in wild-type cultured astrocytes, whereas the ability of L-AP4 to inhibit RANTES was greatly decreased in astrocyte cultures from mGluR4 knockout mice (Besong et al. (2002) Journal of Neuroscience, 22:5403-5411).
• positive allosteric modulators of mGluR4 may be an effective treatment for neuroinflammatory disorders of the central nervous system, including multiple sclerosis and related disorders.
• mGluR4 receptors Two different variants of the mGluR4 receptor are expressed in taste tissues and may function as receptors for the umami taste sensation (Monastyrskaia et al (1999) Br. J Pharmacol. 128:1027-1034; Toyono et al (2002) Arch. Histol. Cytol. 65:91-96).
• positive allosteric modulators of mGluR4 may be useful as taste agents, flavour agents, flavour enhancing agents or food additives.
• vagal afferents innervating gastric muscle express group III mGluRs (mGluR4, mGluR ⁇ , mGluR7 and mGluR8) and actively transport receptors to their peripheral endings (Page et al (2005) 128:402-10). Recently, it was shown that the activation of peripheral group III mGluRs inhibited vagal afferents mechanosensitivity in vitro which translates into reduced triggering of transient lower oesophagal sphincter relaxations and gastroesophageal reflux in vivo (Young et al (2008) Neuropharmacol 54:965-975).
• the compounds of general formula I show potent activity and selectivity on mGluR4 receptor.
• the compounds of the invention demonstrate advantageous properties over compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the invention: the potency on the target, the selectivity for the target, the bioavailability, the brain penetration, and the activity in behavioural models.
• the present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR4 modulators.
• the invention relates to compounds having metabotropic glutamate receptor 4 modulator activity.
• the present invention provides a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:
• n is an integer ranging from 1 to 3;
• a m radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -NO 2 , -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 - C 7 )cycloalkyl, -(C 3 -C 8 )cycloalkenyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, -(Ci- C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-OR
• Any two radicals of A m may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(d-C 6 )alkylhalo, -(d-C 6 )alkyl, -(Ci-C 6 )alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C 6 )alkylaryl;
• R any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from the group of C and N representing 5 membered heteroaryl ring which may further be substituted by 1 to 3 radicals B n ;
• n is an integer ranging from 1 to 3;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -NO 2 , -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 - C 7 )cycloalkyl, -(C 3 -C 8 )cycloalkenyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, -(Ci- C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl-OR
• Any two radicals of B n may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Cs)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C3- Cy)cycloalkyl, -(C 4 -Cio)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl; Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
• R 9 , R 10 , R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-C6)alkyl, -(C 1 - C ⁇ )alkylcyano, -(C3-C7)cycloalkyl, -(C4-Cio)alkylcycloalkyl, heteroaryl, -(Ci- C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl; provided that:
• M 1 when M 1 is aryl, M 2 is H, X 1 and X 4 are C, X 2 is S, X 3 is N, Y 1 , Y 2 and Y 3 are C, Y 4 is NH, n is 1 and B 1 is alkyl substituted on Y 1 then M 3 can not be an optionally substituted -S(O) 2 aryl; and provided that:
• the invention provides a compound according to Formula (II),
• n is an integer ranging from 1 to 3;
• a m radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -NO 2 , -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 2 -C 5 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 - C 7 )cycloalkyl, -(C 3 -C 8 )cycloalkenyl, -(Ci-C 6 )alkylcyano, -(C 1 -C 6 )alkylheteroaryl, -(Ci- C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-
• R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(d-C 6 )alkyl, -(Ci-C 6 )alkylcyano, -(C 3 - C ⁇ )cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl;
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -NO 2 , -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 2 -C 6 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 -
• Any two radicals of B n may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(d-C 6 )alkylhalo, -(d-C 6 )alkyl, -(C 1 -C 6 )alkylcyano, -(C 3 - Cy)cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C6)alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ )alkylaryl;
• R 5 , R 6 , R 7 or R 8 Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
• R 9 , R 10 , R 11 and R 12 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-C6)alkyl, -(C 1 - C 6 )alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -Cio)alkylcycloalkyl, heteroaryl, -(Ci- Ce)alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl; provided that:
• M 1 can not be an aryl optionally substituted by -O-(Ci-Cs)alkyl; and provided that:
• M 3 can not be an optionally substituted -S(O) 2 aryl;
• the invention provides a compound according to Formula (III),
• X 1 is selected from C or N which may further be substituted by A 1 ;
• a 1 radical is selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci- C 6 )alkylhalo, -(C 2 -C 6 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 7 )cycloalkyl, -(C 3 - C8)cycloalkenyl, -(Ci-Ce)alkylcyano, -(Ci-C6)alkylheteroaryl, -(Ci-C6)alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-OR 1 , -NR 1 (C 2 -C 6
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C6)alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl;
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of - (Ci-C 6 )alkyl, -(C 1 -C 6 )alkylhalo, -(C 2 -C 6 )alkynyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 7 )cycloalkyl, - (C 3 -C 8 )cycloalkenyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, -(Ci-C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl; Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• R 9 and R 10 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkylhalo, -(Ci-C ⁇ 5)alkyl, -(Ci-Ce)alkylcyano, -(C3-C7)cycloalkyl, -(C 4 -Cio)alkylcycloalkyl, heteroaryl, -(Ci-C6)alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl; provided that:
• M 1 can not be an aryl optionally substituted by -O-(C]-C 8 )alkyl; and provided that:
• M 3 can not be an optionally substituted -S(O) 2 aryl.
• the invention provides a compound according to Formula (III-A),
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN,
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
• R and R are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - C7)cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C6)alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl; provided that according to proviso (ii): when M 1 is aryl, n is 1, B 1 is alkyl then M 3 can not be an optionally substituted -
• the invention provides a compound according to Formula (HI-B),
• a 1 radical is selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci- C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, -(C 1 - C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(Co-C ⁇ alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-OR 1 , - NR 1 (C 2 -C 6 )alkyl-OR 2 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -O-(C 3 -C
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - C ⁇ )cycloalkyl, -(C 4 -Ci o)alkylcycloalkyl, heteroaryl, -(d-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl;
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of - (Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci- C6)alkylheteroaryl, -(Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, -(Co-Ce)alkyl-OR 5 , -O-(C 2 -C 6 )alkyl-OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -0-(C 3 - C
• M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;
• R 9 and R 10 are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-C6)alkyl, -(Ci-Ce)alkylcyano, -(C 3 -C 7 )cycloalkyl, -(C 4 -Cio)alkylcycloalkyl, heteroaryl, -(Ci-Ce)alkylheteroaryl, aryl, heterocycle and -(Ci-Ce)alkylaryl; provided that according to proviso (i): when M 3 is H, A 1 is H, n is 1 and B 1 is -CN then M 1 can not be an aryl optionally substituted by -O-(d-C 8 )alkyl.
• the invention provides a compound according to Formula (III-B), wherein :
• a 1 radical is selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci- C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci-C 6 )alkylheteroaryl, -(C 1 - C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-OR 1 , - NR 1 (C 2 -C 6 )alkyl-OR 2 , -(C3-C 7 )cycloalkyl-(Ci-C 6 )alkyl, -O-(C
• R 1 , R 2 , R 3 and R 4 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C6)alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - d)cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl;
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of - (Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci- C6)alkylheteroaryl, -(Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, -(Co-Ce)alkyl-OR 5 , -O-(C 2 -C 6 )alkyl-OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -0-(C 3 - C
• R 5 , R 6 , R 7 and R 8 are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C ⁇ )alkylhalo, -(Ci-Ce)alkyl, -(Ci-Ce)alkylcyano, -(C3- Cy)cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ 5)alkylaryl;
• R 5 , R 6 , R 7 or R 8 Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl;
• R and R are selected from the group of a hydrogen or an optionally substituted radical selected from the group of -(Ci-C 6 )alkylhalo, -(Ci-Ce)alkyl, -(Ci-Ce)alkylcyano, -(C3-C7)cycloalkyl, -(C4-Cio)alkylcycloalkyl, heteroaryl, -(Ci-C6)alkylheteroaryl, aryl, heterocycle and -(Ci-C6)alkylaryl; provided that according to proviso (i): when M 3 is H, A 1 is H, n is 1 and B 1 is -CN then M 1 can not be an aryl optionally substituted by -O-(Ci-C 8 )alkyl.
• the invention provides a compound according to Formula (III-B), wherein :
• a 1 radical is selected from the group of hydrogen, halogen, -CN, -OH, -CF3, -SH, -NH 2 and an optionally substituted radical selected from the group of -(Ci-C 6 )alkyl, -(Ci- C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci-Ce)alkylheteroaiyl, -(C 1 - C 6 )alkylaiyl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 1 , -O-(C 2 -C 6 )alkyl-OR 1 , - NR 1 (C 2 -C 6 )alkyl-OR 2 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -O
• R Any two radicals of R (R 1 , R 2 , R 3 or R 4 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• n is an integer ranging from 1 to 2;
• B n radicals are each independently selected from the group of hydrogen, halogen, -CN, -OH, -CF 3 , -SH, -NH 2 and an optionally substituted radical selected from the group of - (Ci-C 6 )alkyl, -(Ci-C 6 )alkylhalo, -(C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylcyano, -(Ci- C 6 )alkylheteroaryl, -(Ci-C 6 )alkylaryl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 )alkyl-OR 5 , -O-(C 2 -C 6 )alkyl-OR 5 , -NR 5 (C 2 -C 6 )alkyl-OR 6 , -(C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl, -
• R , R , R and R are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-C ⁇ )alkylhalo, -(Ci-Ce)alkyl, -(Ci-C6)alkylcyano, -(C 3 - C 7 )cycloalkyl, -(C 4 -C io)alkylcycloalkyl, heteroaryl, -(Ci-C 6 )alkylheteroaryl, aryl, heterocycle and -(Ci-C ⁇ )alkylaryl;
• R 5 , R 6 , R 7 or R 8 Any two radicals of R (R 5 , R 6 , R 7 or R 8 ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;
• M 1 is selected from an optionally substituted 3 to 10 membered ring selected from the group of heteroaryl, heterocyclic and cycloalkyl;
• Particular preferred compounds of the invention are compounds as mentioned in the following list (List of Particular Preferred Compounds), as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemical ⁇ isomeric form thereof and an N-oxide form thereof.
• (C I -C O ) means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
• (Co-C ⁇ ) means a carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
• C means a carbon atom
• N means a nitrogen atom
• O means an oxygen atom
• S means a sulphur atom.
• a subscript is the integer 0 (zero) the radical to which the subscript refers, indicates that the radical is absent, i.e. there is a direct bond between the radicals.
• bonds refers to a saturated covalent bond.
• bonds When two or more bonds are adjacent to one another, they are assumed to be equal to one bond.
• alkyl includes both straight and branched chain alkyl radicals and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t- hexyl.
• (Co-C3)alkyl refers to an alkyl radical having 0, 1, 2 or 3 carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.
• cycloalkyl refers to an optionally substituted carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems.
• fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo- fused carbocycles.
• Cycloalkyl includes such fused ring systems as spirofused ring systems.
• cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fiuorenyl and 1,2,3,4-tetrahydronaphthalene and the like.
• (C3-Cv)cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• alkenyl includes both straight and branched chain alkenyl radicals.
• (C 2 -C 6 )alkenyl refers to an alkenyl radical having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i- pentenyl and hexenyl.
• alkynyl includes both straight and branched chain alkynyl radicals.
• aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like.
• heteroaryl refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S.
• heteroaryl may be, but are not limited to thienyl, pyridyl, thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzoimidazolyl, benzooxazolyl,benzothiazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, benzothiophenyl,
• alkylaryl refers respectively to a substituent that is attached via the alkyl radical to an aryl, heteroaryl or cycloalkyl radical, respectively.
• (Ci- C 6 )alkylaryl includes aryl-Ci-C ⁇ -alkyl radicals such as benzyl, 1 -phenylethyl, 2- phenylethyl, 1 -phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1 -naphthylmethyl and 2- naphthylmethyl.
• (Ci-C 6 )alkyheteroaryl includes heteroaryl-Ci-C ⁇ -alkyl radicals, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1- imidazolylmethyl, 2-imidazolylmethyl, 3-imidazolylmethyl, 2-oxazolylmethyl, 3- oxazolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 1-quinolylmethyl or the like.
• heterocycle refers to an optionally substituted, monocyclic or bicyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom selected independently from N, O and S.
• a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
• rings may be, but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl, thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, cyclohexyl, cyclopentyl,
• a 3- to 10-membered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
• Such rings may be, but are not limited to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, eye Io butyl, azetidinyl, oxadia
• alkylhalo means an alkyl radical as defined above, substituted with one or more halo radicals.
• (C 1 - Ce)alkylhalo may include, but is not limited to, fiuoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
• the term "O-Ci-C ⁇ -alkylhalo” may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy and fluoro ethoxy.
• alkylcyano means an alkyl radical as defined above, substituted with one or more cyano.
• optionally substituted refers to radicals further bearing one or more substituents which may be, but are not limited to, (Ci-C6)alkyl, hydroxy, (Ci-C6)alkyloxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, amidinyl, carboxyl, carboxamide, (Ci-Ce)alkyloxycarbonyl, carbamate, sulfonamide, ester and sulfonyl.
• solvate refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and a solvent.
• the solvent is a pharmaceutically acceptable solvent as preferably water; such solvent may not interfere with the biological activity of the solute.
• positive allosteric modulator of mGluR4" or “allosteric modulator of mGluR4" refers also to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemical ⁇ isomeric form thereof and an N-oxide form thereof.
• Allosteric modulators of mGluR4 described herein, and the pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
• Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
• the allosteric modulators of mGluR4 will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the compounds of the instant invention can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995).
• the amount of allosteric modulators of mGluR4, administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used CNS drugs are well known to the skilled person.
• the total daily dose usually ranges from about 0.05 - 2000 mg.
• the present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose.
• the compositions may be administered by any suitable route.
• parenterally in the form of solutions for injection topically in the form of onguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, intranasally or transcutaneously in the form of delivery system like patches.
• the allosteric modulators of mGluR4 thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
• the tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• the disclosed allosteric modulators of mGluR4 can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
• solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the compounds may also be formulated as a depot preparation.
• Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly or by intramuscular injection.
• implantation for example, subcutaneously or intramuscularly or by intramuscular injection.
• sparingly soluble derivatives for example, as sparingly soluble salts.
• Preferably disclosed allosteric modulators of mGluR4 or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal.
• the unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet, or a vial.
• the quantity of active ingredient in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient.
• the dosage will also depend on the route of administration which may be by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal.
• the compounds according to the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M. (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I) to (III-B).
• the compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or S-enantiomers. If for instance, a particular enantiomer is required, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
• a basic functional group such as an amino or an acidic functional group such as carboxyl
• this resolution may be conveniently performed by fractional crystallization from various solvents as the salts of an optical active acid or by other methods known in the literature (e.g. chiral column chromatography).
• an intermediate or a starting material may be performed by any suitable method known in the art (Eliel E.L., Wilen S.H. and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley-Interscience). Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A.R. and. Rees CW. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).
• the product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization and distillation.
• the compounds of the invention may be prepared by general route of synthesis as disclosed in the following methods.
• compounds of Formula (III-A) may be prepared according to the synthetic sequences illustrated in Scheme 1.
• Pyrazole gl can be protected (PG: protecting group), for example, by /?-methoxybenzyl or tert- butyloxycarbonyl using standard conditions.
• amidine can be synthesized either from ester treated with aluminium chloride in the presence of ammonium chloride or from nitrile by synthesis of amidoxime g3 followed by hydrogenation, in the presence of Pd/C and anhydride acetic. Under these conditions of reduction, the protecting group te/t-butyloxycarbonyl is removed.
• amidine g4 and isothiocyanate g5 may be promoted by di-?er ⁇ -butylazodicarboxylate and a base such as DBU.
• aminothiadiazole g6 can be deprotected when PG is /)-methoxybenzyl in the presence of TFA with a solvent such as dichloroethane under reflux.
• the compounds of Formula (III-B) may be prepared according to the synthetic sequences illustrated in Scheme 2.
• Compound g8 may be hydro lyzed by standard procedures followed by reaction with oxalyl chloride to yield compound glO.
• the acid chloride can be transformed in bromoketone gll via the formation of diazoketone.
• Thiourea gl2 can be generated either from a primary amine treated first with benzoylisothiocyanate followed by basic treatment (Press et al (2005) Bioorg. Med. Chem. Let.
• the compounds of Formula (HI-B) may be prepared according to the synthetic sequences illustrated in Scheme 3.
• Compound g9 may be converted into Weinreb amide gl5 which undergoes addition of Grignard reagent to yield ketone gl6.
• ketone gl6 can be transformed into bromoketone gl7 in presence of CuBr2.
• the cyclization reaction may be performed between bromoketone gl7 and thiourea 12 to yield the aminothiazole gl8.
• g20 can be deprotected with classical conditions.
• compounds of Formula (III-B) may be prepared in accordance with Scheme 4.
• Thiazole ring in compound gl3 can be substituted either by chloride in the presence of N-chlorosuccinimide or by fluoride using Select-Fluor. Then compound g22 can be obtained after deprotection in the presence of TFA using thermic or microwave conditions.
• Scheme 4 In another embodiment of the present invention compounds of Formula (III-B) may be prepared in accordance with Scheme 5. Bromoketone gll can be converted into cyanoketone g23 in the presence of KCN. Then the cyclization reaction may be performed between cyanoketone g23 and thiourea gl2 to yield the aminothiazole g24. Finally, g24 can be deprotected with classical conditions well known to people skilled in the art.
• compounds of Formula (III-B) may be prepared in accordance with Scheme 6.
• pyrazole g27 undergoes coupling with enolether g28 in the presence of Pd(O Ac)2 and silver carbonate.
• the subsequent ketone g29 in the presence of thiourea gl2 may be cyclized into thiazole g30 which can be deprotected with classical conditions.
• compounds of Formula (III-B) may be prepared in accordance with Scheme 7. After Sonogashira coupling between alkyne g32 and iodopyrazole g27, triple bond in compound g33 is transformed into methyl ketone in the presence of SnCi2. The subsequent ketone g34 is first brominated and then cyclised in the presence of thiourea gl2 into thiazole g36.
• compounds of Formula (III-B) may be prepared in accordance with Scheme 8.
• Methyl alcohol can be introduced on the thiazole ring from compound gl4 using formaldehyde in the presence of a base such as EtsN under microwaved conditions as described in WO2007/031440A2.
• Scheme 8 In another embodiment of the present invention compounds of Formula (III-B) may be prepared in accordance with Scheme 9.
• a well known procedure to synthetise pyrazole is from ketoester g38 which is condensed with l,l-dimethoxy-N,N- dimethylmethanamine followed by cyclisation in the presence of hydrazine.
• Pyrazole g40 can be protected by p-methoxybenzyl using standard conditions. Then compound g41 may be hydro lyzed by standard procedures followed by reaction with oxalyl chloride to yield compound g43. Subsequently, the acid chloride can be transformed in bromoketone g44 via the formation of diazoketone. Then the cyclization reaction may be performed between thiourea gl2 and bromoketone g44 to yield aminothiazole g45. Finally, g45 can be deprotected with classical conditions.
• compounds of Formula (III) may be prepared according to Scheme 10.
• g47 may be acylated in the presence of anhydride acetic in a solvent such as pyridine or with an acid chloride in the presence of a base such as EtsN in a solvent such as THF.
• Scheme 10 In one embodiment of the present invention compounds of Formula (III) may be prepared according to Scheme 11. g47 may be converted into urea by treatment either with potassium cyanate as described in Yang et al (2004) J. Med. Chem. 47 (6): 1547- 1552, or with carbamic chloride in the presence of a base such as DBU or with isocyanate.
• compounds of Formula (III) may be prepared according to Scheme 12.
• g47 may be sulfonylated by sulfonyl chloride in the presence of a base such as Et3N to yield pyrazole g50.
• compounds of Formula (II) may be prepared in accordance with Scheme 13.
• Pyrazole g51 can be protected by p- methoxybenzyl using standard conditions.
• compound g53 may be coupled to 2,6- dibromopyridine via Suzuki coupling followed by nucleophilic substitution of primary amine in presence of a base such as KOrBu.
• g55 can be deprotected with classical conditions.
• AIl references to brine refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in 0 C (degrees Centigrade). All reactions are conducted not under an inert atmosphere at room temperature unless otherwise noted.
• Method B A mixture of tert-hvXyl 4-cyano-3-methyl- lH-pyrazole-1-carboxylate (7.96 mmol, 1.65 g) and hydroxylamine 50% in water (15.9 mmol, 0.98 mL) and EtOH (20 mL) was heated at 80 0 C for 4 hours. After evaporation of the solvent, 1.90 g (7.91 mmol, 99%) of fert-butyl-4-(N'-hydroxycarbamimidoyl)-3- methyl-lH-pyrazole-1-carboxylate was obtained. The crude product was used in the next step without purification.
• Step 3 DBU (0.26 mmol, 0.04 mL) was added to a solution of l-chloro-2-isothiocyanatobenzene (0.26 mmol, 34 ⁇ l) and 3 -methyl- lH-pyrazole-4- carboxamidine acetate (0.26 mmol, 60 mg) in DMF (5 mL) under nitrogen. The reaction mixture was stirred at room temperature until total consumption of the amidine. Then, di-terz-butylazodicarboxylate (0.26 mmol, 60 mg) was added dropwise and the reaction mixture was stirred for 5 minutes. Then a solution of NaOH 3M (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the EtOH, water was added and the aqueous phase was extracted with
• Step 1 A suspension of ethyl 5 -propyl- lH-pyrazole-4- carboxylate (2.74 mmol, 500 mg), l-(bromomethyl)-4-methoxybenzene (2.74 mmol, 0.39 niL) and K 2 CO 3 (2.74 mmol, 379 mg) in acetonitrile (10 mL) was heated at 7O 0 C overnight. Water was added and the aqueous phase was extracted with AcOEt. The organic phase was washed with water and brine, was dried over Na 2 SO 4 , was filtered and was concentrated under reduced pressure.
• the crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to afford a mixture of ethyl 1 -(4-methoxybenzyl)-3 -propyl- 1 H-pyrazo le-4-carboxylate and o f ethyl l-(4-methoxybenzyl)-5-propyl-lH-pyrazole-4-carboxylate (2.15 mmol, 650 mg, 78%) as an orange oil.
• Step 3 DBU (567 ⁇ mol, 86.3 mg) was added to a solution of a mixture of l-(4-methoxybenzyl)-3 -propyl- lH-pyrazole-4-carboximidamide and of 1- (4-methoxybenzyl)-5-propyl-lH-pyrazole-4-carboximidamide (567 ⁇ mol, 175 mg), and isothiocyanatobenzene (567 ⁇ mol, 76.6 mg) in dry DMF, under argon. The reaction mixture was stirred at room temperature until total consumption of the amidine. Then, di-terf-butylazodicarboxylate (567 ⁇ mol, 130 mg) was added dropwise and was stirred for 5 minutes.
• Step 4 A solution of a mixture of 3-(l-(4-methoxybenzyl)-3- propyl-lH-pyrazol-4-yl)-N-(pyridin-2-yl)-l,2,4-thiadiazol-5-amine and of 3-(l-(4- methoxybenzyl)-5 -propyl- lH-pyrazol-4-yl)-N-(pyridin-2-yl)- 1 ,2,4-thiadiazo 1-5 -amine (0.39 mmol, 160 mg) in TFA (2 mL) and dichloroethane (2 mL) was stirred under reflux for 12 hours.
• Step 1 Triphenylphosphine (11 mmol, 2.9 g), (4- methoxyphenyl)methanol (10 mmol, 1.4 g) and di-tert-butylazodicarboxylate (11 mmol, 2.6 g) were added to a solution of 3-methyl-lH-pyrazol-4-carbonitrile (9.3 mmol, 1.0 g), in DCM (40 mL) at O 0 C. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with a saturated solution of NH 4 OH and brine. Then the organic phase was dried over MgSO 4 , was filtered and was concentrated under reduced pressure.
• the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90: 10) as eluent to yield a mixture of l-(4-methoxybenzyl)-3 -methyl- lH-pyrazol-4-carbonitrile and of l-(4- methoxybenzyl)-5-methyl-lH-pyrazol-4-carbonitrile (9.3 mmol, 2.1g, 100%).
• Step 2 The compound was prepared according to Example 1 Step 2, Method B from a mixture of l-(4-methoxybenzyl)-3 -methyl- lH-pyrazo 1-4- carbonitrile and of l-(4-methoxybenzyl)-5-methyl-lH-pyrazol-4-carbonitrile (9.30 mmol, 2.1 g). Reaction conditions: 12 hours at 80 0 C.
• the title compound was prepared from a mixture of (N'-hydroxy- 1 -(4-methoxybenzyl)- 3-methyl-lH-pyrazole-4-carboximidamide and of (N r -hydroxy-l-(4-methoxybenzyl)-5- methyl-lH-pyrazole-4-carboximidamide (9.30 mmol, 2.42 g). Reaction conditions: 12 hours at room temperature.
• Step 4 The title compound was prepared prepared according to Example 2 Step 4, from a mixture of 3 -(l-(4-methoxybenzyl)-3 -methyl- lH-pyrazo 1-4- yl)-N-(pyridin-2-yl)-l,2,4-thiadiazol-5 -amine and of l-(4-methoxybenzyl)-5-methyl- lH-pyrazole-4-carboximidamide (0.11 mmol, 43 mg). 11 mg (43 ⁇ mol, 37%) of 3-(3- methyl-lH-pyrazol-4-yl)-N-(pyridin-2-yl)-l,2,4-thiadiazol-5-amine were obtained as a white solid.
• EXAMPLE 4 7V-(Pyridin-2-yl)-4-(3-(trifluoromethyl)- lH-pyrazol-4-yl)thiazol-2- amine (Final Compound 1-12) l-(4-Methoxybenzyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid and l-(4- methoxybenzyl)-3-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid
• Step 1 A solution of a mixture of ethyl 1 -(4-methoxybenzyl)- 5-(trifluoromethyl)-lH-pyrazole-4-carboxylate and of ethyl l-(4-methoxybenzyl)-3- (trifluoromethyl)-lH-pyrazole-4-carboxylate (2.80 mmol, 0.92 g) and LiOH (28.0 mmol, 1.20 g) in water/T ⁇ F (1 :1, 20 mL) was heated at 80 0 C overnight.
• Step 2 A solution of a mixture of l-(4-methoxybenzyl)-5- (trifluoromethyl)-lH-pyrazole-4-carboxylic acid and of l-(4-methoxybenzyl)-3-
• reaction mixture was stirred at room temperature overnight.
• HBr (9.9 mmol, 1.1 mL, 48%) was added at O 0 C to the reaction mixture.
• the reaction mixture was stirred at room temperature for one hour. After evaporation of the solvent, AcOEt was added and the aqueous phase was neutralized with a solution of NaOH 1 M. The aqueous phase was extracted with AcOEt.
• Step 4 A solution of a mixture of 2-bromo- 1 -(I -(4- methoxybenzyl)-3-(trifluoromethyl)- lH-pyrazol-4-yl)ethanone and of 2-bromo- 1 -( 1 -(4- methoxybenzyl)-5-(trifluoromethyl)-lH-pyrazol-4-yl)ethanone (0.95 mmol, 0.15 g) and of 1 -(pyridin-2-yl)thiourea (1.19 mmol, 0.45 g) in acetone (15 mL) was stirred under reflux overnight.
• Step 5 A solution of a mixture of 4-(l-(4-methoxybenzyl)-3- (trifluoromethyl)-lH-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amme and of 4-(l-(4- methoxybenzyl)-5-(trifluoromethyl)-lH-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine (0.58 mmol, 0.25 g) in TFA (3 mL) was stirred under reflux for 12 hours (or microwaved for 10 min at 150 0 C).
• Step 1 A solution of l-(4-methoxybenzyl)-lH-pyrazole-4- carboxylic acid (34.4 mmol, 8.00 g), oxalyl chloride (68.9 mmol, 5.92 mL) and a drop of DMF in DCM (80 mL) was stirred for 1 hour at room temperature.
• Step 2 Ethylmagnesium bromide (3 ⁇ , 37.2 mmol, 12.4 mL) was added dropwise at room temperature to a solution of N-methoxy- 1 -(4- methoxybenzyl)-N-methyl-lH-pyrazole-4-carboxamide (33.8 mmol, 9.30 g) in T ⁇ F (80 mL) and the reaction mixture was stirred for 1 hour. Then ethylmagnesium bromide (3N, 37.2 mmol, 12.4 mL) was added and the reaction mixture was stirred for 1 hour.
• Step 4 A solution of 2-bromo-l-(l-(4-methoxybenzyl)-lH- pyrazol-4-yl)propan-l-one (23.8 mmol, 7.70 g) and of 1 -(pyridin-2-yl)thiourea (26.2 mmol, 4.02 g) in EtOH (200 mL) was stirred under reflux overnight. The reaction was quenched with water (200 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSC> 4 , was filtered and was concentrated to yield a brown solid.
• reaction mixture was diluted with AcOEt (250 mL) and the organic phase was washed with a saturated solution OfNa 2 COs. The organic phase was dried over MgSO/i, was filtered and was concentrated to yield N-(4-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-5-chlorothiazol-2-yl)pyridin-2-amine (1.16 mmol, 460 mg, 84%) as a beige solid.
• Step 1 Method B: Select-Fluor (0.13 mmol, 48 mg) was added portionwise to a solution of 4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-N-(pyridin-2- yl)thiazol-2-amine (0.27 mmol, 100 mg) and of 2,6-dimethylpyridine (0.27 mmol, 32 ⁇ L) in DMF (3 mL) at 0 0 C. The reaction mixture was stirred at room temperature for 6 hours.
• Step 1 A solution of l-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-2-bromoethanone (9.70 mmol, 3.00 g) and potassium cyanide (14.6 mmol, 948 mg) in 120 mL of water/MeO ⁇ /T ⁇ F (1 : 1 : 1) was stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (150 mL) and the aqueous phase was extracted with DCM.
• Step 2 A solution of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-3-oxopropanenitrile (9.40 mmol, 2.40 g) and of 1 -(pyridin-2-yl)thiourea (9.40 mmol, 1.44 g) in pyridine (30 mL) was stirred at 80 0 C for 1 hour. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with DCM.
• Step 3 A solution of 4-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-2-(pyridin-2-ylamino)thiazol-5-carbonitrile (0.93 mmol, 360 mg) in TFA (3 mL) was microwaved for 5 min at 140 0 C. The reaction mixture was neutralized with a saturated solution of Na 2 CC ⁇ (40 mL) and water (50 mL). The aqueous phase was filtered to afford a brown solid which was recrystallized thrice with DMF/water to yield
• Step 1 A suspension of 4-iodo-lH-pyrazole (26.3 mmol, 5.11 g), l-(chloromethyl)-4-methoxybenzene (29.0 mmol, 3.95 mL) and K2CO3 (39.5 mmol, 5.46 g) in acetonitrile (150 mL) was heated at 6O 0 C overnight. The reaction mixture was cooled to room temperature and was filtered. The filtrate was concentrated under reduced pressure.
• Step 3 A solution of 3,3,3-trifluoro-l-(l-(4-methoxybenzyl)- lH-pyrazol-4-yl)propan-l-one (2.51 mmol, 750 mg), l-(pyridin-2-yl)thiourea (2.51 mmol, 385 mg) and of iodine (2.51 mmol, 638 mg) in pyridine (15 mL) was stirred at 9O 0 C for 6 hours. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSOzt, was filtered and was concentrated to yield a brown solid.
• Step 1 A solution of 4-iodo-l-(4-methoxybenzyl)-lH-pyrazole (4.78 mmol, 1.50 g), ethynylbenzene (6.21 mmol, 0.68 mL), PdCl 2 (PPh 3 ) 2 (0.24 mmol, 168 mg) and CuI (0.48 mmol, 91 mg) in diethylamine (30 mL) was stirred at 5O 0 C for 3 hours. The reaction was quenched with water (150 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO 4 , was filtered and was concentrated to yield a brown solid.
• the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to yield after evaporation l-(4-methoxybenzyl)-4-(phenylethynyl)-lH-pyrazole (3.92 mmol, 1.13 g, 82%) as a beige solid.
• Step 2 A solution of l-(4-methoxybenzyl)-4-(phenylethynyl)- lH-pyrazole (3.12 mmol, 900 mg), SnCl 2 (12.5 mmol, 2.37 g) and of HCl (37%, 20 mL) in EtOH (20 mL) was stirred overnight at 90 0 C. The reaction was quenched with water (100 niL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSC> 4 , was filtered and was concentrated to yield a brown solid.
• Step 4 A solution of 2-bromo-2-phenyl-l-(lH-pyrazol-4- yl)ethanone (0.23 mmol, 60 mg) and of l-(pyridin-2-yl)thiourea (0.23 mmol, 35 mg) in EtOH (4 mL) was stirred at 90 0 C overnight. The reaction was quenched with a saturated solution of Na 2 COs (50 mL) and the aqueous phase was extracted with DCM/MeO ⁇ (90:10, 5OmL). The organic phase was dried over MgS ⁇ 4 , was filtered and was concentrated to yield a brown solid.
• EXAMPLE 12 4-(3-Ethyl-lH-pyrazol-4-yl)-7V-(pyridin-2-yl)thiazol-2-amine (Final Compound 1-61)
• Step 1 A solution of ethyl 3-oxopentanoate (13.9 mmol, 2.00 g) and of l,l-dimethoxy-7V,N-dimethylmethanamine (13.9 mmole, 1.84 mL) in DMF (10 mL) was microwaved for 30 min at 120 0 C. After evaporation of the solvent, 2.76 g (13.9 mmol) of (£)-ethyl 2-((dimethylamino)methylene)-3-oxopentanoate were obtained and used without further purification.
• Step 2 A solution of ( ⁇ )-ethyl 2-((dimethylamino)methylene)- 3-oxopentanoate (13.9 mmol, 2.76 g) and hydrazine (13.9 mmol, 0.44 mL) in EtOH (50 niL) was stirred for 1 hour at room temperature. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to yield after evaporation ethyl 3-ethyl-lH- pyrazole-4-carboxylate (6.00 mol, 1.01 g, 43%) as a yellow oil.
• Step 3 A suspension of ethyl 3-ethyl-lH-pyrazole-4- carboxylate (5.95 mmol, 1.0 g), l-(chloromethyl)-4-methoxybenzene (6.54 mmol, 0.89 mL) and K 2 CO 3 (17.8 mmol, 2.46 g) in acetone (20 mL) was heated at 60 0 C overnight. After evaporation of the solvent, water was added and the aqueous phase was extracted with DCM. The organic phase was dried over Na 2 SOzI, was filtered and was concentrated under reduced pressure.
• the crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (95:5) as eluent to afford a mixture of ethyl 5-ethyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate and of ethyl 3-ethyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate (2.77 mmol, 800 mg, 47%) as a yellow oil.
• Step 4 A solution of LiOH (8.32 mmol, 356 mg) in water (4 mL) was added to a solution of a mixture of ethyl 5-ethyl-l-(4-methoxybenzyl)-lH- pyrazole-4-carboxylate and of ethyl 3-ethyl-l-(4-methoxybenzyl)-lH-pyrazole-4- carboxylate (2.77 mmol, 800 mg) in MeO ⁇ /T ⁇ F (1:1, 5 mL) and the reaction mixture was heated at 80 0 C for 3 hours. After evaporation of the solvent, HCl 2 M was added and the aqueous phase was extracted with DCM.
• Step 5 A solution of a mixture of 3-ethyl-l-(4- methoxybenzyl)-lH-pyrazole-4-carboxylic acid and of 5-ethyl-l-(4-methoxybenzyl)- lH-pyrazole-4-carboxylic acid (2.77 mmol, 722 mg), thionyl chloride (8.32 mmol, 0.60 mL) and drops of DMF in DCM (10 mL) was stirred for 1 hour at room temperature.
• Step 6 A solution of TMSdiazomethane (6.10 mmol, 3.05 mL) was added to a solution of a mixture of 3-ethyl-l-(4-methoxybenzyl)-lH-pyrazole-4- carbonyl chloride and of 5-ethyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carbonyl chloride (2.77 mmol, 0.77 g) in acetonitrile (10 mL) at 0 0 C. The reaction mixture was stirred at room temperature overnight. HBr (9.71 mmol, 1.1 mL, 48%) was added at O 0 C to the reaction mixture. The reaction mixture was stirred at room temperature overnight.
• Step 7 A solution of a mixture of 2-bromo-l-(3-ethyl-l-(4- methoxybenzyl)-lH-pyrazol-4-yl)ethanone and of 2-bromo-l-(5-ethyl-l-(4- methoxybenzyl)-lH-pyrazol-4-yl)ethanone (1.19 mmol, 400 mg) and of 1 -(pyridin-2- yl)thiourea (1.19 mmol, 182 mg) in EtOH (2.5 mL) was stirred
• Step 8 A solution of a mixture of 4-(3-ethyl-l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine and of 4-(5-ethyl-l- (4-methoxybenzyl)-lH-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine (1.18 mmol, 464 mg) in TFA (0.5 mL) was microwaved for 5 min at 14O 0 C. The crude residue was neutralized with a saturated solution of Na 2 COs and the aqueous phase was extracted with DCM.
• the resulting crude product was purified by flash chromatography over silica gel using DCM/MeO ⁇ (99: 1) as eluent to yield after evaporation 2-methyl- 1 -(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)- lH-pyrazol- 1 -yl)propan- 1 -one (0.16 mmol, 53 mg, 42%) as an off-white solid.
• EXAMPLE 18 5-Methyl-4-(l-(methylsu]fonyl)-lH-pyrazol-4-yl)- ⁇ -(pyridin-2- yl)thiazol-2-amine (Final Compound 1-45)
• Step 1 A suspension of 4-(4,4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)-lH-pyrazole (7.38 mmol, 1.43 g), 1 -(chloromethyl)-4- methoxybenzene (7.38 mmol, 1.00 mL) and K2CO3 (7.38 mmol, 1.02 g) in acetonitrile (10 mL) was heated at 8O 0 C for 5 hours. Water was added and the aqueous phase was extracted with DCM.
• Step 2 Pd(PPh 3 ) 4 (0.42 mmol, 488 mg) was added to a solution of l-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (4.22 mmol, 1.33 g), 2,6-dibromopyridine (4.22 mmol, 1.00 g) and of a 2 M solution of K 3 PO 4 (6.33 mL) in DME (10 mL). The reaction mixture was stirred at
• Step 3 A solution of 2-bromo-6-(l -(4-methoxybenzyl)- IH- pyrazol-4-yl)pyridine (0.58 mmol, 200 mg), 2,5-difluoroaniline (0.58 mmol, 58 ⁇ L) and KO ⁇ Bu (0.58 mmol, 65 mg) in toluene (5 mL) was stirred for 15 hours at 100 0 C.
• Step 4 A solution of N-(2,5-difluorophenyl)-6-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)pyridin-2-amine (0.26 mmol, 100 mg) in TFA (5 mL) was microwaved for 10 min at 120 0 C. A saturated solution Of NaHCO 3 was added to the reaction mixture and the precipitate formed was filtered and dried.
• Reversed phase HPLC was carried out on an Zorbax SB-C 18 cartridge (3.5 ⁇ m, 4.6 x 50 mm) from Agilent, with a flow rate of 1 mL/min.
• the gradient conditions used are: 95 % A (water + 0.5% of formic acid), 5% B (acetonitrile + 0.5 % of formic acid) to 100 % B at 5.0 minutes, kept till 6.0 minutes and equilibrated to initial conditions at 6.5 minutes until 7.5 minutes. Injection volume 5-20 ⁇ L.
• ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltage was 30 V for both positive and negative ionization modes.
• Reversed phase HPLC was carried out on an Zorbax SB-Cl 8 cartridge (1.8 ⁇ m, 4.6 x 30 mm) from Agilent, with a flow rate of 1.5 mL/min.
• the gradient conditions used are: 90 % A (water + 0.05 % of formic acid), 10% B (acetonitrile + 0.05 % of formic acid) to 100 % B at 3.5 minutes, kept till 3.7 minutes and equilibrated to initial conditions at 3.8 minutes until 4.5 minutes.
• ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltage was 30 V for both positive and negative ionization modes.
• the compounds provided in the present invention are positive allosteric modulators of mGluRA As such, these compounds do not appear to bind to the orthosteric glutamate recognition site, and do not activate the mGluR4 by themselves. Instead, the response of mGluR4 to a concentration of glutamate or mGluR4 agonist is increased when compounds of Formula I to III are present. Compounds of Formula I to III are expected to have their effect at mGluR4 by virtue of their ability to enhance the function of the receptor.
• the compounds of the present invention are positive allosteric modulators of mGluR4 receptor. Their activity was examined on recombinant human mGluR4a receptors by detecting changes in intracellular Ca 2+ concentration, using the fluorescent Ca 2+ -sensitive dye Fluo4-(AM) and a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA)
• the cDNA encoding the human metabotropic glutamate receptor (hmGluR4) was subcloned into an expression vector containing also the hygromycin resistance gene.
• the cDNA encoding a G protein allowing redirection of the activation signal to intracellular calcium flux was subcloned into a different expression vector containing also the puromycin resisitance gene.
• HEK-293 cells expressing hmGluR4 were maintained in media containing DMEM, dialyzed Fetal Calf Serum (10 %), GlutamaxTM (2 mM), Penicillin (100 units/mL), Streptomycin (100 ⁇ g/mL), Geneticin (100 ⁇ g/mL) and Hygromycin-B (40 ⁇ g/mL) and puromycin (1 ⁇ g/mL) at 37°C/5%CO 2 .
• Human mGluR4 HEK-293 cells were plated out 24 hours prior to FLIPR 384 assay in black-walled, clear-bottomed, poly-L-ornithine-coated 384-well plates at a density of 25,000 cells/well in a glutamine/glutamate free DMEM medium containing foetal bovine serum (10 %), penicillin (100 units/mL) and streptomycin (100 ⁇ g/mL) at 37 C/5 % CO 2 .
• the medium was aspirated and the cells were loaded with a 3 ⁇ M solution of Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03 % pluronic acid. After 1 hour at 37 C/ 5 % CO 2 , the non incorporated dye was removed by washing cell plate with the assay buffer and the cells were left in the dark at room temperature for six hours before testing. All assays were performed in a pH 7.4 buffered- solution containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mM MgSO 4 , 1 mM CaCl 2 , 0.125 mM sulfapyrazone, 0.1 % glucose.
• the Table 5 below represents the mean EC50 obtained from at least three independent experiments of selected molecules performed in duplicate.
• the positive allosteric modulators provided in the present invention are expected to increase the effectiveness of glutamate or mGluR4 agonists at mGluR4 receptor. Therefore, these positive allosteric modulators are expected to be useful for treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such positive allosteric modulators.
• Typical examples of recipes for the formulation of the invention are as follows: 1. Tablets
• active ingredient can be replaced by the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
• An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 mL.
• a parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol and water.
• active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

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